(Supported by N01-NS-5-2324, N01-DC-5-2105, N01-NS-5-2333 and N01-DC-7-2103 to William F. Agnew) The development of neuroprosthetic devices in humans is an important research strategy that promises to lead to the reduction of human disabilities including loss of hearing and vision, equilibrium disturbances and impaired of bladder function. We are developing neurprosthetic devices that will provide electrical stimulation to specific brain and spinal cord regions. We apply microscopy, including LM, CTEM, IVEM and HVEM and elemental analysis, as well as cytochemical and immunocytochemical methods. Our studies are intended to determine the margins of safety and optimum electrical stimulation parameters, and to understand the mechanisms of electrically-induced tissue damage, as well as to assess the biocompatibility of the implanted electrodes. High-voltage electron microscopy has proved an important adjunct to our methodological approach, providing valuable three -dimension al, stereo-pair images of neuronal, glial , synaptic and vascular components of the nervous tissue exposed to electrical stimulation. The previous studies of Tivol et al., (J. Neurosci. Methods 19, 1987), established the framework for continuing an investigation of the effects of iridium electrodes on the surrounding neural tissues. An important part of our study in determining safe and effective electrical stimulation is to determine not only physiological (activation) thresholds but also to determine the "therapeutic" window. To do this, we must exceed physiologic stimulus intensities; i.e., find not only the neural damage threshold but also the threshold for damage to the microelectrodes themselves. For example, in the collaboration mentioned previously, using high-voltage microanalysis, we described the alloy P130Ir as a suitable material for chronic pulsing, due to the finding of crystalline platinum and iridium in the tissues. We are re-evaluating present stimulation techniques which are now using multisite stimulating electrodes. Energy-dispersive X-ray microanalysis spectra and micrographs were recorded with the IVEM from sections sent by Dr. Lossinsky. The data was sent to Dr. Lossinsky for submission with a grant proposal